Sorin Avram

Romanian Academy · Department of Computational Chemistry

DrugCentral monitors new drug approvals and standardizes drug information. The current update contains 285 drugs (131 for human use). New additions include: (i) the integration of veterinary drugs (154 for animal use only), (ii) the addition of 66 documented off-label uses and iii) the identification of adverse drug events from pharmacovigilance da...

Physicians have the freedom to prescribe medicines outside the list of approved indications, to treat mild to life-threatening clinical conditions and diseases, particularly when conventional treatments fail or are lacking. Off-label drug usage is more frequently observed in specific populations not often represented in clinical trials, e.g., pedia...

Drug repurposing is the development of existing drugs for new uses: given that 9 in 10 drugs that enter drug development are never marketed and therefore represent wasted effort, it is an attractive as well as inherently more efficient process. Three repurposed drugs can be brought to market for the same cost as one new chemical entity; and they ca...

In cheminformatics, protein-ligand docking is a powerful tool applied for virtual screening, pose prediction, and binding affinity estimation. However, docking results depend on the quality of the crystal protein structures. Although several crystallographic indices can assist the selection of proteins, these are often misused by non-experts or hav...

In the context of unknowing the experimental structure for histamine H3 receptor, which is a potential therapeutical target for numerous disorders and diseases, the theoretical methods can bring light and necessary information for a better understanding of the pharmacological implications of the aforementioned receptor. Thus, a homology model of hu...

This study aims to provide a first large-scale comparison between the various diffraction-component precision index (DPI) equations, assess the applicability of the parameter, and make recommendations on DPI computation. The DPI estimates the average accuracy of atomic coordinates obtained by the structural refinement of protein diffraction data, w...

DrugCentral is a public resource (http://drugcentral.org) that serves the scientific community by providing up-to-date drug information, as described in previous papers. The current release includes 109 newly approved (October 2018 through March 2020) active pharmaceutical ingredients in the US, Europe, Japan and other countries; and two molecular...

Drug repositioning aims to reuse 'old' drugs to treat diseases outside their approved indication(s). Composition-of-matter patents and FDA exclusivities can hinder the immediate availability of some drugs to be repositioned (repurposed). Here, we analyze data from the FDA Orange Book and use current on-market patent validity and exclusivities to cl...

Interaction signatures of drug candidates are characteristic to off-target (neutral) and antitarget (negative) effects, inferring reduced efficiency, side-effects and high attrition rate. Today’s retroactive scaled-down virtual screening (VS) experiments relying on benchmarking datasets are extensively involved to assess ligand enrichment in the re...

The current work was conducted to investigate the effectiveness of two conceptually distinct in silico ligand‐based tools: Partial Least Squares Discriminant Analysis (PLS‐DA) and 3D similarity, including shape, physico‐chemical and electrostatics to classify target‐specific pharmacophores with enrichment power for selective GSK‐3 inhibitors agains...

The striking structural resemblance between adenosine triphosphate (ATP) binding sites of glycogen synthase kinase-3 (GSK-3) and cyclin-dependent kinase-2 (CDK-2) raises numerous off-target selectivity problems in lead-identification processes that may jeopardize their progress into safe and effective drugs. The structural disparities between GSK-3...

Lately, the cancers related with abnormal hedgehog (Hh) signalling pathway are targeted by smoothened (SMO) receptor inhibitors that are rapidly developing. Still, the problems of known inhibitors such as severe side effects, weak potency against solid tumors or even the acquired resistance need to be overcome by developing new suitable inhibitors....

In this work an in silico study based on 2D and 3D similarity methodologies and a benchmarking data set made up of experimentally confirmed actives including selective and nonselective inhibitors and inactives for glycogen synthase kinase 3 (GSK-3) was performed. The results obtained highlight the relevance of 3D shape and the so-called "color" fea...

Purpose The growing amount of heterogeneous bioactivity data requires effective strategies to assess the promiscuity/selectivity of small-molecules and aid drug discovery. In the current study, we aim to evaluate the potential of assay profiles (APs, i.e., unique combinations of assay-related features describing how activity determinations were per...

Colon cancer is a widespread pathology with complex biochemical etiology based on a significant number of intracellular signaling pathways that play important roles in carcinogenesis, tumor proliferation and metastasis. These pathways function due to the action of key enzymes that can be used as targets for new anticancer drug development. Herein w...

Model: 2016, 56, 895-905; www.chembioinf.ro), aiming to build and measure the performance of ligand-based kinase inhibitor prediction models. Here, we analyzed kinase-inhibitor pairs with multiple activity points extracted from ChEMBL database, and identified the main sources of inconsistency. Our results indicate that lower IC50 values are usuall...

The current study was conducted to elaborate a novel pharmacophore model to accurately map selective glycogen synthase kinase-3 (GSK-3) inhibitors, and perform virtual screening and drug repurposing. Pharmacophore modeling was developed using PHASE on a data set of 203 maleimides. Two benchmarking validation data sets with focus on selectivity were...

Angiogenesis plays an important function in tumor proliferation, one of the main angiogenic promoters being the vascular endothelial growth factor (VEGF) which activates specific receptors, particularly VEGFR-2. Thus, VEGFR-2 has become an essential therapeutic target in the development of new antitumor drugs. 1,2,4-triazoles show a wide range of b...

The extensive biochemical research of multiple types of cancer has revealed important enzymatic signaling pathways responsible for tumor occurrence and progression, thus compelling the need for the discovery of new means with which to block these signaling cascades. The phosphoinositide?3-kinase/ protein kinase?B?(PI3K/AKT) pathway, which plays an...

In this study we developed two dimensional pharmacophore-based random forest models for the effective profiling of kinase inhibitors. One hundred seven prediction models were developed to address distinct kinases spanning over all kinase groups. Rigorous external validation demonstrates excellent virtual screening and classification potential of th...

In this study the fungicidal activity, expressed as relative inhibition rate, was correlated with trifluoromethyl-1,2,4-triazole derivative descriptors by the Partial Least Squares (PLS) method. For a data set containing 18 structures, previously modeled by the RM1 semiempirical quantum chemical method, various electronic and 0D, 1D, 2D and 3D desc...

In this study, we aim to model inhibitors of the dual specificity mitogen-activated protein kinase kinase 1 (MEK 1), which acts as a key component of the mitogenactivated protein kinase signal transduction pathway modulating cell growth in various types of tumors. We applied supervised self-organizing map (SOM) modeling using topological autocorrel...

Several series of substituted maleimide derivatives (3-anilino-4-aryl, indolyl, oxaindolyl), and macrocyclic maleimides were reported as potent, selective GSK-3 inhibitors. In order to gain overall insight into structural prerequisites that influence biological activity, we adopted a ligand-based methodology - three-dimensional quantitative structu...

In search for anticancer drugs, numerous laboratory studies and human clinical trials showed that flavonoids have important effects on cancer chemoprevention and chemotherapy. Flavonoids have been considered as mapping agents to guide the development of small molecule probes for enzyme catalytic sites which establish key structural features for pot...

Understanding the relationship between the biological behavior of high throughput screening hits and their chemical profile is an important task in the drug discovery process. This work presents a methodology for deciphering the biological promiscuity of high throughput screening hits (frequent hitters) via their chemical behavior. To achieve this...

Cutaneous melanoma is one of the most violent forms of skin cancer due to high malignant potential. Advances in molecular therapeutic approaches are still confronted with resistance and very low survival [1]. More efficient, with low toxicity, natural agents are studied for their chemopreventive and anti-tumor potential. Here, we investigated two p...

The design of chemical libraries, an early step in agrochemical discovery programs, is frequently addressed by means of qualitative physicochemical and/or topological rule-based methods. The aim of this study is to develop quantitative estimates of herbicide- (QEH), insecticide- (QEI), fungicide- (QEF), and, finally, pesticide-likeness (QEP). In th...

Context: Glycogen synthase kinase-3 (GSK-3) overactivity was correlated with several pathologies including type 2 diabetes mellitus, Alzheimer's disease, cancer, inflammation, obesity, etc. Objective: The aim of the current investigation was to model the inhibitory activity of maleimide derivatives--inhibitors of GSK-3, to evaluate the impact of...

Flavonoids, the vastest class of natural polyphenols, are extensively investigated for their multiple benefits on human health. Due to their physicochemical or biological properties, many representatives are considered to exhibit low selectivity among various protein targets or to plague high-throughput screening (HTS) outcomes. The aim of this stu...

Mortality LD50 values of a series of 37 pyrethroidal esters have been previously measured against a susceptible strain of housefly (Musca domestica). Structural features of these compounds were related to the LD50 values by multiple linear regression (MLR) to see their influence on mortality. Pyrethroidal esters structures were first built by the M...

Polyhydroxylated chalcones are able to efficiently inhibit aldose reductase (ALR2; EC 1.1.1.21), an enzyme implicated in the development of diabetic complications. In this study, we performed docking experiments on a series of 38 2′-hydroxy and 2′,4′-dihydroxychalcones with measured inhibitory activities. We demonstrate that docking the chalcones i...

Partial Least Squares Discriminant Analysis (PLS-DA) is employed to obtain novel combinations of energetic terms present in classical scoring functions, which exceed and compensates the “traditional” consensus scheme. These novel scoring functions were involved to rank the database of indirubin inhibitors of glycogen synthase kinase-3β and cyclin d...

In this study, a simple evaluation metric, denoted as eROCE was proposed to measure the early enrichment of predictive methods. We demonstrated the superior robustness of eROCE compared to other known metrics throughout several active to inactive ratios ranging from 1:10 to 1:1000. Group fusion similarity search was investigated by varying 16 simil...

The current study describes the development of in silico models based on a novel alternative of the MTD-PLS methodology (Partial-Least-Squares variant of Minimal Topologic Difference) developed by our group to predict the inhibition of GSK-3β by indirubin derivatives. The new MTD-PLS methodology involves selection rules for the PLS equation coeffic...

In silico screening algorithms are frequently included in drug discovery programs because a significant number of drug candidates have been detected through structure and ligand-based algorithms. In the current work 337 maleimide derivatives that are inhibitors and noninhibitors of GSK-3a/b were successfully investigated by means of a projection to...

Neutrophil elastase, a serine proteinase from the chymotrypsin family, has been the object of comprehensive experimental and theoretical studies to develop efficient human neutrophil elastase inhibitors. The serine protease has been linked to the pathology of a variety of inflammatory diseases, making it an attractive target for the development of...

GSK-3 (Glycogen synthase kinase-3) is a serine/threonine protein kinase involved in various physiological processes and its inhibitors have been evaluated as promising drug candidates for severe pathologies. In this paper a PLS regression analysis was used, to explore the relationship between field of descriptors (as independent variable) and biolo...

A series of 36 substituted 2-phenylindoles was analysed using minimal topological difference-projections in latent structures variant (MTD-PLS) and molecular docking, using fast rigid exhaustive docking (FRED) and AutoDock Vina programs. For quantitative structure activity relationships (QSAR) validation, a sphere exclusion algorithm in the multi-d...

Docking studies have become popular approaches in drug design, where the binding energy of the ligand in the active site of the protein is estimated by a scoring function. Many promising techniques were developed to enhance the performance of scoring functions including the fusion of multiple scoring functions outcomes into a so-called consensus sc...

Fingerprint-based similarity search provides an efficient way to perform virtual screenings on large databases. This paper evaluates the performance of four similarity coefficients on the VEGFr2 DUD subset. We found the Forbes similarity coefficient to slightly outperform the other coefficients in all the studied aspects: early enrichment, overall...